1,720,957 research outputs found
Computational study targeting anti-fungal Tavaborole analogs and anti-cancer BRACO19
Full text linkThis thesis comprises of three computer aided drug design studies utilizing molecular docking and molecular dynamic simulations: (i) a lead optimization study virtually screening an initial library of ~120000 lead compounds targeting fungal leucyl tRNA synthetase, (ii) an exploratory study to understand the binding pathway of BRACO19 to a parallel telomeric DNA G-quadruplex by MD simulations and compare with experimentally solved X-ray crystal structure (iii) a comparative study to understand the lack of selectivity of BRACO19 to various topologies of human telomeric DNA G-quadruplex over DNA duplex.
The first chapter provides the background information required to understand the molecular docking studies and molecular dynamics simulation (MD) studies conducted and discussed in this thesis. This introductory chapter is organized as follows: the first section is an introduction to molecular recognition in protein-ligand interactions, the second section introduces computer-aided drug design, the third section introduces homology modelling, the fourth section discusses molecular docking and virtual screening, the fifth section introduces methods for binding affinity prediction and the sixth section explains MD simulations.
The second chapter of this thesis proposes a library of compounds with enhanced activity compared to the parent molecule it had been modified from. Tavaborole, the recently approved topological anti-fungal drug, inhibits leucyl tRNA synthetase by irreversible covalent bonding and hinders protein synthesis. The benzo-boroxole pharmacophore of tavaborole is responsible for its unique activity. This study theoretically proposes molecules with improved anti-fungal affinity.
The third chapter of this thesis explores the binding pathway of anti-cancer drug, BRACO19 and human telomeric DNA G-quadruplex. G-quadruplex specific ligands that stabilizes the G-quadruplex, have great potential to be developed as anticancer agents. A free human telomeric DNA G-quadruplex and an unbound BRACO19 are simulated and the resulting structure is then compared with an experimentally solved X-ray structure of human telomeric G-quadruplex with a bound BRACO19 intercalated within the G-quadruplex. Three binding modes have been identified: top end stacking, bottom intercalation and groove binding. Bottom intercalation mode (51% of the population) is identical to the binding pose in the X-ray solved crystal structure.
The fourth chapter of this thesis compares different topological folds of human telomeric DNA G-quadruplexes (parallel, antiparallel and hybrid) that have been experimentally solved using molecular dynamic simulation to understand the 62-fold preferential selectivity of BRACO19 towards human telomeric DNA G-quadruplex over DNA duplex. Groove binding mode was found to be the most stable binding mode for the duplex and top stacking mode for the G-quadruplexes. The non-existential binding selectivity of BRACO19 can be accounted to the similar groove binding to both the duplex and the G-quadruplex. For that reason, a modification should be induced such that this prospective ligand destabilizes binding to the duplex but stabilizes the G-quadruplex binding
Synthesis of Pillar[n]arenes and Bridge-Functionalized Pillar[n]arenes via Cyclic and Acyclic Acetals
No full textPillar[n]arenes are macrocyclic compounds consisting of ‘n’ hydroquinone units linked by para-methylene bridges. Since their first report of facile synthesis 17 years ago, pillararenes have attracted significant interest due to their versatile functionality, electron-rich cavity, crystalline nature, and planar chirality. These unique properties have enabled a broad range of practical applications, including small molecule separation, formation of one-dimensional and two-dimensional channels, drug delivery systems, and enhanced emissive and fluorescent properties. The ease of synthesis of pillararenes has been one of the key factors in their widespread adoption and continued exploration in supramolecular chemistry and material science. Despite the efficiency and broad substrate scope of traditional pillararene synthesis, it relies exclusively on paraformaldehyde as the source of methylene bridges. However, paraformaldehyde releases formaldehyde, a known carcinogen, at ambient conditions causing safety concerns. In this study, we demonstrated that cyclic and acyclic acetals of formaldehyde serve as safer and nonaqueous alternatives to paraformaldehyde. This novel approach preserves the efficiency and simplicity of traditional pillararene synthesis while significantly improving safety by reducing formaldehyde exposure. Using paraformaldehyde for pillararene synthesis does not allow for substitutions on the methylene bridge of pillararenes. This limitation can be addressed by employing acetals. This study demonstrated that using cyclic acetals of acetaldehyde as the bridge source allowed for the synthesis of methyl-substituted-methine-bridged pillar[6]arenes. Notably, introducing a methine bridge introduced chiral centers and shifted the thermodynamic equilibrium towards one stereoisomer of the corresponding pillar[6]arene, providing access to a stereoselective synthetic protocol for pillar[6]arene with an improved yield of 43%. This strategy significantly enhances the safety profile of pillararene synthesis and expands the structural diversity of pillararenes. This broadened diversity could lead to more applications across various fields
Synthesis of Pillar[n]arenes and Bridge-Functionalized Pillar[n]arenes via Cyclic and Acyclic Acetals
No full textPillar[n]arenes are macrocyclic compounds consisting of ‘n’ hydroquinone units linked by para-methylene bridges. Since their first report of facile synthesis 17 years ago, pillararenes have attracted significant interest due to their versatile functionality, electron-rich cavity, crystalline nature, and planar chirality. These unique properties have enabled a broad range of practical applications, including small molecule separation, formation of one-dimensional and two-dimensional channels, drug delivery systems, and enhanced emissive and fluorescent properties. The ease of synthesis of pillararenes has been one of the key factors in their widespread adoption and continued exploration in supramolecular chemistry and material science. Despite the efficiency and broad substrate scope of traditional pillararene synthesis, it relies exclusively on paraformaldehyde as the source of methylene bridges. However, paraformaldehyde releases formaldehyde, a known carcinogen, at ambient conditions causing safety concerns. In this study, we demonstrated that cyclic and acyclic acetals of formaldehyde serve as safer and nonaqueous alternatives to paraformaldehyde. This novel approach preserves the efficiency and simplicity of traditional pillararene synthesis while significantly improving safety by reducing formaldehyde exposure. Using paraformaldehyde for pillararene synthesis does not allow for substitutions on the methylene bridge of pillararenes. This limitation can be addressed by employing acetals. This study demonstrated that using cyclic acetals of acetaldehyde as the bridge source allowed for the synthesis of methyl-substituted-methine-bridged pillar[6]arenes. Notably, introducing a methine bridge introduced chiral centers and shifted the thermodynamic equilibrium towards one stereoisomer of the corresponding pillar[6]arene, providing access to a stereoselective synthetic protocol for pillar[6]arene with an improved yield of 43%. This strategy significantly enhances the safety profile of pillararene synthesis and expands the structural diversity of pillararenes. This broadened diversity could lead to more applications across various fields
Cyclic and Acyclic Acetals as Safe, Nonaqueous Formaldehyde Equivalents for the Synthesis of Pillararenes
Full text linkPillar[5]arene was synthesized using acyclic acetals diethoxymethane and dimethoxymethane, and cyclic acetals 1,3-dioxolane and 1,3,5-trioxane as an alternative to paraformaldehyde. Both Lewis and Brønsted acids were effective in catalyzing the hydrolysis of acetal and initiating the Friedel–Crafts reaction in pillararene synthesis
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
